Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA.
Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX 77843, USA.
Int J Mol Sci. 2021 Oct 21;22(21):11379. doi: 10.3390/ijms222111379.
Virus-induced neurological sequelae resulting from infection by Theiler's murine encephalomyelitis virus (TMEV) are used for studying human conditions ranging from epileptic seizures to demyelinating disease. Mouse strains are typically considered susceptible or resistant to TMEV infection based on viral persistence and extreme phenotypes, such as demyelination. We have identified a broader spectrum of phenotypic outcomes by infecting strains of the genetically diverse Collaborative Cross (CC) mouse resource. We evaluated the chronic-infection gene expression profiles of hippocampi and thoracic spinal cords for 19 CC strains in relation to phenotypic severity and TMEV persistence. Strains were clustered based on similar phenotypic profiles and TMEV levels at 90 days post-infection, and we categorized distinct TMEV response profiles. The three most common profiles included "resistant" and "susceptible," as before, as well as a "resilient" TMEV response group which experienced both TMEV persistence and mild neurological phenotypes even at 90 days post-infection. Each profile had a distinct gene expression signature, allowing the identification of pathways and networks specific to each TMEV response group. CC founder haplotypes for genes involved in these pathways/networks revealed candidate response-specific alleles. These alleles demonstrated pleiotropy and epigenetic (miRNA) regulation in long-term TMEV infection, with particular relevance for resilient mouse strains.
由 Theiler's 鼠脑脊髓炎病毒 (TMEV) 感染引起的病毒诱发的神经后遗症，被用于研究从癫痫发作到脱髓鞘疾病等人类疾病。根据病毒持续存在和极端表型（如脱髓鞘），通常认为小鼠品系对 TMEV 感染敏感或具有抗性。通过感染遗传多样性协作交叉 (CC) 小鼠资源的品系，我们确定了更广泛的表型结果谱。我们评估了 19 个 CC 品系的慢性感染基因表达谱与表型严重程度和 TMEV 持续时间的关系，分别为海马体和胸脊髓。根据表型相似性和 90 天感染后 TMEV 水平对品系进行聚类，并对不同的 TMEV 反应谱进行分类。三种最常见的类型包括“抗性”和“敏感”，与以前一样，以及一种“有弹性”的 TMEV 反应组，即使在 90 天感染后，也经历了 TMEV 的持续存在和轻度神经表型。每个谱都有独特的基因表达特征，允许识别每个 TMEV 反应组特有的途径和网络。涉及这些途径/网络的基因的 CC 创始者单倍型揭示了候选反应特异性等位基因。这些等位基因在长期 TMEV 感染中表现出多效性和表观遗传（miRNA）调节，对有弹性的小鼠品系尤其相关。
